Early Environmental Contributions to Adult Onset Obesity

描述（由申请人提供）：代谢性疾病，如肥胖和II型糖尿病，是现代美国社会的症状性疾病，仅肥胖一项目前每年就产生960亿美元的直接卫生费用。5年内，美国将有三分之一的成年人肥胖。虽然基因型明显有助于肥胖的易感性，但环境决定了其表现。胎儿环境是人类常见成人疾病的关键因素，如心脏病、高血压、II型糖尿病和肥胖。通过使用辅助生殖技术生产的动物在成年后容易肥胖。自1995年以来，已有超过100万人通过某种形式的辅助生殖技术受孕。虽然这些人目前很少成年，但大多数人都表现出临床肥胖的迹象。众所周知，体外培养环境会改变动物和人类卵母细胞和胚胎的能量代谢。这项研究的长期目标是确定体外培养环境如何影响导致成人肥胖的体内平衡系统。迄今为止，大多数关于代谢性疾病的研究都改变了怀孕成年女性的环境。本研究的创新之处在于通过体外成熟和体外受精技术来控制早期发育环境；从而可以研究环境对早期胚胎的影响，以及对成年动物的后续影响。虽然培养基中导致肥胖的成分尚不清楚，但酒精是许多辅助生殖技术程序中使用的一种常见成分。我们实验室的结果表明，小鼠在卵母细胞体外成熟过程中特异性暴露于乙醇，成年后逐渐肥胖。为了确定哪些生理系统参与了这种成年型肥胖，将使用一个全面的笼子代谢监测系统，以及基因表达的变化来确定暴露于酒精的小鼠与对照组相比能量调节的变化。这些实验将有助于阐明在早期母体和胚胎环境中建立的影响成年疾病易感性的系统和途径，如肥胖和II型糖尿病。

DESCRIPTION (provided by applicant): Metabolic diseases, such as obesity and type II diabetes, are symptomatic illnesses of modern American society and obesity alone currently accrues $96 billion of direct health costs per year. Within 5 years, a third of adults in the US will be obese. While genotypes clearly contribute to the predisposition for obesity, it is the environment that determines its manifestation. Fetal environment is a critical factor for common adult diseases in humans, such as heart disease, high blood pressure, type II diabetes, and obesity. Animals produced through the use of assisted reproductive technology are susceptible to obesity in adulthood. Over a million people, since 1995, have been conceived using some form of assisted reproductive technology. Although few of these people have reached adulthood presently, most show signs of clinical obesity. The in vitro culture environment is known to alter the energy metabolism of oocytes and embryos in animals, as well as humans. The long-term goal of this proposed study is to determine how the in vitro culture environment affects homeostatic systems that lead to adulthood obesity. Most studies to date of metabolic disease alter the environment of the pregnant adult female. This study is innovative in that the early developmental environment will be controlled by using in vitro maturation and in vitro fertilization techniques; thereby allowing investigation of environmental influence on the early embryo, and the subsequent effects on the resulting adult animal. Although the constituents in culture media leading to obesity are not known, alcohol is one common component used in many assisted reproductive technology procedures. Results from our laboratory suggest that mice specifically exposed to ethyl alcohol during in vitro maturation of oocytes gradually become obese in adulthood. To pinpoint which physiological systems are involved in this adult-onset obesity, a comprehensive cage metabolic monitoring system, as well as changes in gene expression will be used to identify the alternations in energy regulation of mice exposed to alcohol as compared to controls. These experiments will help to elucidate the systems and pathways which are established within the early maternal and embryonic environment that influence a predisposition to adulthood diseases, such as obesity and type II diabetes.